Deciphering the Mechanisms of Pain in Paget’s Disease

Principal Investigator: Professor Stuart Ralston from the Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh.

in 2017, the Paget’s Association awarded a grant to facilitate research into pain as it is the most common symptom in Paget’s Disease of Bone, occurring in about 73% of patients who come to medical attention. In some patients, the pain seems to be due to abnormalities in a process called bone remodelling which is essential for maintaining healthy bones. In Paget’s disease, the bone remodelling process is accelerated greatly and this can sometimes be associated with pain. However, for reasons that are unclear, many patients with Paget’s who have accelerated bone remodelling, don’t experience pain, and others experience pain where the rates of bone remodelling appear to be normal.

The lack of understanding of pain mechanisms is reflected in the fact that pain continues to be a significant issue in Paget’s patients, despite treatment with drugs called bisphosphonates, which are highly effective at correcting abnormalities in bone remodelling. The reasons are unclear but possibilities are that irreparable damage to the bone has already occurred by the time of presentation; that the bone pain is not due to increased renewal and repair of bone, but to other causes such as an alteration in pain thresholds; or that some of the factors that are responsible for stimulating bone renewal and repair in Paget’s disease have direct effects on pain pathways. This study will investigate these possibilities. The team will carefully evaluate a group of 300 patients with Paget’s disease, some of whom have pain and others who do not, with the aim of identifying the clinical and biochemical characteristics of patients who have pain and those who do not. Next, they will focus on patients who do have pain and categorise these individuals into subgroups based on the likely cause of the pain. This information will be used to develop a personalised treatment package for patients with pain. The researchers will then investigate the evolution of Paget’s disease in relation to the development of pain, in participants of a clinical trial (the ZiPP study), which is already in progress. The aim of this will be to identify, at an early stage, whether there are any blood tests or other  characteristics that can be used to predict the development of pain and to determine whether early treatment with the bisphosphonate zoledronic acid, influences symptoms of pain.

The outcome of the programme of research will be to gain a much greater understanding of pain mechanisms than we have at present, and to apply this knowledge to improve quality of life for patients already affected with Paget’s disease and their children, who may be at risk of developing Paget’s disease.